TW568784B - Pharmaceutical composition for treating nasal polyps and Widal's syndrome comprising H+, K+-ATPase inhibitor - Google Patents
Pharmaceutical composition for treating nasal polyps and Widal's syndrome comprising H+, K+-ATPase inhibitor Download PDFInfo
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- TW568784B TW568784B TW086114622A TW86114622A TW568784B TW 568784 B TW568784 B TW 568784B TW 086114622 A TW086114622 A TW 086114622A TW 86114622 A TW86114622 A TW 86114622A TW 568784 B TW568784 B TW 568784B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Description
568784 A7 ______」7 五、發明説明（1 ) 一 ----- 本發明的範圍 (請先閲讀背面之注意事項再填寫本頁) 本1月楗供一種利用質子幫浦抑制劑（外亦即η+ κ+_ ATP酶抑制劑，治療息肉病的新方法。 ， 發明背景 息肉病通常發生於鼻部及消化道中。鼻内的息肉病爲發 、、；鼻肽之白色袅狀組織。此白色通常肇因於血液的補充 不艮。我們並不清楚何物導至此息肉病的發生，但是息肉 病的出現$伴隧特定的醫學症狀，如氣喘或阿斯匹靈過 敏。鼻部息肉病對一般人而言發生率較低，約僅i %。然 而13%的氣喘患者及36%對阿斯匹靈過敏之氣喘患者患有 鼻邵息肉病。鼻部息肉病、氣喘及阿斯匹靈敏感，三種病 症即爲已知的葦德氏症候群（Widal，s syndr〇me)。 經濟部中央標準局員工消費合作社印製 鼻部息肉病的治療一般分爲二期。首先可藉由手術或施 以局4鼻内類固醇製劑，如倍他米松（betamethas〇ne)嶙酸 鈉鹽，以縮小息肉的體積。一旦息肉的體積縮小，接著需 定期施以鼻内類固醇喷劑-如倍氣米松（becl〇methas〇me)、 布松奈budesonide或弗卡松（fluticasone)丙酸鹽，以維持長 時間的效果。若需要快速改善，可口服類固醇-如潑尼松 龍（prednisonide)、地氣美松（dexmethasone)或合成之促腎 上腺皮質激素（見V.J.倫德之’’鼻部息肉病之診斷與治療” (V.J. Lund, Diagnosis and treatment of nasal polyps) Birt Med J 1995,111，1411-4)亦有文獻提出使用非類固醇消炎藥 物治療鼻部息肉病（見WO 97〇3659_A)。 本發明的詳細描述 -4- 本紙張尺度適用中國國家標準（CNS ) A4規格T 2!0X297公釐) ~ " 一 568784 五、發明説明（2 根據本發明係提供一種治療鼻部息肉病的方法，此方法 包括對患有該症狀的患者施以h+，k+-atp酶抑制劑，本發 明更進一步提供Η，K -ATP酶抑制劑在製造治療鼻部息肉 病之藥物上的用途。 Η，Κ -ΑΤΡ酶抑制劑爲一種已知常用於治療與胃酸有關 之疾病的藥劑屬於Η+，Κ+-ΑΤΡ酶抑制劑的已知實例之俗名 爲：歐米哌唑（omepraz〇le)，榔色哌唑（lans〇praz〇le)，本達 哌唑（pantoprazole)拉比哌唑（rabepraz〇ie)與雷諾哌唑 (leminoprazole)。其中有些化合物已揭示於例如：^-^· 0005129，EP-A1-174726，EP-A1-166287及 GB2163747。 這些醫藥物質通常已知·藉由在酸分泌管遒的最後階段控 制θ故分析，因此適用於抑制哺乳動物或人類之胃酸分 泌。因此，更一般而言，它們可用於預防或治療哺乳動物 或人類與胃酸有關的疾病，包括：逆流性食道炎、胃炎、 十二指腸炎、胃潰瘍及十二指腸潰瘍。 我們目前很驚訝地發現H+，k\atp酶抑制劑適用於治療 鼻部息肉病，特別在已知的治療方法失敗時。 較適用於本發明的H+，K+-ATP酶抑制劑爲如下通式化合物 經濟部中央標準局員工消費合作社印製568784 A7 ______ "7 V. Description of the invention (1) I. The scope of the present invention (please read the precautions on the back before filling this page) This January provides a proton pump inhibitor (external also That is, η + κ + _ ATPase inhibitor, a new method for treating polyposis. BACKGROUND OF THE INVENTION Polyposis usually occurs in the nose and digestive tract. Polyposis in the nose is a white, diarrheal tissue with nasal peptides. This white color is usually caused by blood supplementation. We do not know what caused this polyposis, but the appearance of polyposis is accompanied by specific medical symptoms such as asthma or aspirin allergies. Nasal polyps The incidence of the disease is low for the general population, only about i%. However, 13% of asthmatic patients and 36% of asthmatic patients allergic to aspirin have nasal polyposis. Nasal polyposis, asthma, and aspirin The three diseases are known as Widal (syndrome). The treatment of nasal polyposis printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is generally divided into two phases. First, it can be performed by surgery. Or administer 4 intranasal steroid preparations, such as Betamethasone sodium salt to reduce the volume of polyps. Once the volume of polyps is reduced, it is necessary to regularly apply intranasal steroid sprays-such as beclomethasone and buffon Nephelium budesonide or fluticasone propionate to maintain long-term effects. If rapid improvement is required, steroids such as prednisonide, dexmethasone, or synthetic adrenergic hormones can be taken orally Corticosteroids (see VJ Lund, Diagnosis and treatment of nasal polyps Birt Med J 1995, 111, 1411-4) have also been suggested in the literature to use nonsteroidal anti-inflammatory drugs Treatment of nasal polyposis (see WO 97〇3659_A). Detailed description of the present invention -4- The paper size is applicable to Chinese National Standard (CNS) A4 specification T 2! 0X297 mm) ~ " 568784 V. Description of the invention ( 2 According to the present invention, there is provided a method for treating nasal polyposis, the method comprising administering h +, k + -atp enzyme inhibitors to patients suffering from the symptoms, and the present invention further provides Η, K-ATPase inhibitors in system Pharmacological application for the treatment of nasal polyposis. Κ, κ-ATPase inhibitor is one of the known examples of 常 +, κ + -ATPase inhibitors, which are known to be commonly used to treat gastric acid-related diseases. Common names: Omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds have been disclosed in, for example, ^-^ · 0005129, EP-A1-174726, EP-A1-166287 and GB2163747. These medicinal substances are generally known and analyzed by controlling theta at the final stage of the acid secretion duct, and are therefore suitable for suppressing gastric acid secretion in mammals or humans. Therefore, more generally, they can be used to prevent or treat gastric acid-related diseases in mammals or humans, including: reflux esophagitis, gastritis, duodenitis, gastric ulcers, and duodenal ulcers. We are currently surprised to find that H +, k \ atp enzyme inhibitors are suitable for the treatment of nasal polyposis, especially when known treatments have failed. The H + and K + -ATPase inhibitors that are more suitable for the present invention are compounds of the following formula: printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
Het; Ο II -S—Het 2 (I) 其中Heq爲Het; Ο II -S—Het 2 (I) where Heq is
或 -5- 本紙張尺度適用中國國家標準（CNS ) M規格（οχ297公釐） \Rc (請先閲讀背面之注意事項再填¾本頁)Or -5- This paper size applies to Chinese National Standard (CNS) M specification (οχ297 mm) \ Rc (Please read the notes on the back before filling this page)
568784 A7 B7 夂、發明説明（3 其中1^12爲 且X爲 ——CH- 10568784 A7 B7 发明, description of the invention (3 where 1 ^ 12 is and X is ——CH-10
^8 或 ηι (請先閱讀背面之注意事項再填寫本頁)^ 8 or ηι (Please read the notes on the back before filling this page)
I 在Heh之苯并咪唑中N表示經R6_R9取代之環碳原子之— 視情況可被不含任何取代基之氮原子置換；I in Heh's benzimidazole N represents the ring carbon atom substituted with R6_R9-optionally substituted by a nitrogen atom without any substituent;
Rl及R3分別獨立代表氫、烷基或烷氧基（但R!及R3不可 同時代表烷氧基）；且R2代表烷基，視情況由氟取代之烷 氧基、硫烷基或烷氧烷氧基；或心及心其中之一爲鹵素， 且另一個爲氫，R2爲1 -嗎啉基，丨_六氫吡啶基或二烷胺 基； 於R4及R5爲相同或不同，且選自：氫與烷基；R1 and R3 each independently represent hydrogen, alkyl, or alkoxy (but R! And R3 cannot simultaneously represent alkoxy); and R2 represents alkyl, and optionally alkoxy, sulfanyl, or alkoxy substituted by fluorine An alkoxy group; or one of the core and the heart is halogen, and the other is hydrogen, R2 is 1-morpholinyl, hexahydropyridyl, or dialkylamino; R4 and R5 are the same or different, and Selected from: hydrogen and alkyl;
RrR9爲相同或不同之，且選自氫，鹵素，烷基，烷氧 基，自烷氧基，烷羰基及烷氧羰基； R10爲氫，或Rh^R3 —起構成一個包含6〜8個碳原子的 環；且 R1 1代表氫’卣素或、j：完基； 其中式（I)化合物可視情況呈醫藥上可接受之鹼性鹽或呈 -6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇χ297公釐） 1-]· 經濟部中央標準局員工消費合作社印製 568784 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（4 ) 其中性形式，或爲單一對映異構物物或其外消旋混合物； 其中每一個烷基或烯基部份爲1〜6個碳原子的直鏈或分 支鍵，以1〜4個碳原子較佳； 其中鹵原子爲氟、氯或溴原子較佳，以氟或氯原子較 佳。 特別適用本發明之式（I)化合物實例如下RrR9 is the same or different, and is selected from hydrogen, halogen, alkyl, alkoxy, starting from alkoxy, alkcarbonyl and alkoxycarbonyl; R10 is hydrogen, or Rh ^ R3 together to form one containing 6 to 8 A ring of carbon atom; and R1 1 represents hydrogen or halogen, j: end group; wherein the compound of formula (I) may be a pharmaceutically acceptable basic salt or -6-this paper applies Chinese national standards ( CNS) A4 specification (21 × 297 mm) 1-] · Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 568784 A7 B7 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) Neutral form, or A single enantiomer or a racemic mixture thereof; wherein each alkyl or alkenyl moiety is a straight or branched chain of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; of which The halogen atom is preferably a fluorine, chlorine or bromine atom, and more preferably a fluorine or chlorine atom. Examples of compounds of formula (I) particularly suitable for use in the present invention are as follows
CH3 (la) 9〇h2cf3 ,ch3 〇 、入 OCH3 .OCH, (請先閲讀背面之注意事嗔再填容本頁) Η 〇 n^^%v/〇chf2CH3 (la) 9〇h2cf3, ch3 〇, enter OCH3 .OCH, (Please read the notes on the back 嗔 then fill in this page) Η 〇 n ^^% v / 〇chf2
H 9ch2ch2ch2〇ch2 .CH〇H 9ch2ch2ch2〇ch2 .CH〇
XH2—IXH2—I
H 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 568784 A7 B7 五、發明説明（ 5 ch3H This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 568784 A7 B7 V. Description of invention (5 ch3
N-CH2CH(CH3)2N-CH2CH (CH3) 2
ch2—s—\ I /Hch2—s— \ I / H
HH
HH
(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 h3(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs h3
H3 c 〇 8 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 568784 五、發明説明（6 及H3 c 〇 8 This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 568784 V. Description of the invention (6 and
〇〇
n(ch3)2 經濟部中央標準局員工消費合作社印製 上本發明中所採用的H+，K+-ATP酶抑制劑爲式（la)較佳：換 言之，較佳者爲歐米哌唑，或歐米哌唑的鹼性鹽，歐米哌 峻的㈠對映異構物或其鹼性鹽。 當式（I)化合物視情況需要呈醫藥上可接受之鹼性鹽時， 較佳者爲Mg2+，Ca2+，Na+，K+鹽，以Mg2+鹽更佳。 本發明所採用之H+，K+-ATP酶抑制劑可經口、經直腸、 或非經腸式投藥。雖然口服歐米喊唑之患者對鼻部息肉之 抑制效果已經確認，但咸信此抑制劑對息肉爲全身性效 果，與投藥方式無關。所以採用其它投藥方式應仍可達到 縮小息肉體積的效果。 市售的H+，K+-ATP酶抑制劑之藥劑適用於本發明。此類 歐米哌唑製劑實例包括充填於膠囊内之歐米哌唑的腸溶性 包衣藥丸粒，或調配成系單位藥錠劑型；歐米哌唑或其驗 性鹽的腸溶性包衣藥錠或；及含有歐米哌唑鹼性鹽的非、經 腸式投藥用溶液。 H +，K+-ATP酶抑制劑之投藥劑量，依所治療鼻部息肉的 型態及病人的症狀而異。然而其口服、經直腸、或經靜脈 内投藥的劑量一般爲每日1至1〇〇毫克h+，k+-atp酶抑制 -9- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） J · ^衣-- (請先閱讀背面之注意事項再填寫本頁} 訂 568784 A7 ------_ 五、發明説明（7 ) 〜^ " ---- 劑的範圍。通常口服劑量爲每曰i 〇至4〇亳克。 (請先聞讀背面之注意事項再填寫本頁) 本發明可併用其它已知可改善通常與鼻部息肉病有關的 -匕痖狀，如氣喘的其他治療法。換言之，本發明可施用 於治療葦德氏症候群，其包括的症狀爲鼻部息肉病、氣喘 ，阿斯匹靈敏感。本發明亦可施用於治療其它上呼吸道發 炎的疾病，如急性或慢性鼻竇炎、過敏性或非過敏性鼻 炎、及治療下呼吸道發炎，如氣喘。因此，根據本發明進 一步提供一種治療葦德氏症候群及其他呼吸道發炎疾病之 方法，其包括對患者同時、分開或連續投予包含Η+，κ+_ ATPg母抑制劑及糖皮質激素之醫藥調配物。根據本發明亦 進一步提供一種醫藥調配物，用於以對患者同時、分開或 連續投予包含H+，K+-ATP酶抑制劑及糖皮質激素之調配 物’以治療葦德氏症候群及氣喘。本發明尚提供一種以 h'k'atp酶抑制劑或糖皮質激素於製造此等醫藥調配物 上之用途。 較佳的糖皮質激素爲局部活性的消炎性類固醇。合適的 類固醇實例包括布松奈（budseonide);洛普奈 (roHeponide);洛普奈棕欄酸鹽（rofleponide palmitate);赛 經濟部中央標準局員工消費合作社印製 克奈（ciclesonide);莫美他松糖酸鹽（momethasone fur〇ate);弗地卡松丙酸鹽（fluticasone propionate) ; 16 a，17 α -亞丁基二氧1-6江，9從-^一氣- lly5-，21- —經基孕-1,4-二婦· 3,20-二酮；6 從，9從-二氟-11々-羥基·16α，17α-二亞丁基二 氧-17α-甲硫·雄甾烷-4-烯-3-酮；S-16a，17a-亞丁基二氧 基-6 α，9 α -二氟-11 Θ -羥基-3-氧-雄甾烷-1，4-二烯17 /?-羧 -10- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 568784 A7 B7 五、發明説明（8 ) 硫代酸甲酯；9α-氣-6沈-氟-11從-¾基-16沈-甲基_3-氧-17 π -丙醯氧基-雄甾烷-1，4 -二烯-17 π-複酸甲酯；6 α，9 α _ 二氟- lly5 -¾基-16α -甲基-3-氧-17α -丙醯氧基雄甾嫁-1，4·» 二晞-17<^-叛硫代酸8_(-2-氧-四氫-咬喃-38-基）自旨；狄普丹 (tipredane);膚輕松丙酮化物（fiuocin〇i〇ne acet〇nide);弗 尼索賴（flunisolide);氟甲松（flumethasone);氧美松 (dexamethasone);倍他米松（betamethasone);倍他米松二 丙 fe 鹽（beclomethasone dipropionate);狄弗杳克 (deflazacort);克狄瓦索（cortivazol);或皮質固醇與/或氫化 皮質固醇，視情況呈其純對映異構物型（若該型式存在時） 及是其醫藥上可接受的鹽型。 本發明所使用的類固醇可採用習知之劑量施用，例如每 日40至300微克。投藥方式可爲口服或鼻内吸入。類固醇 可視情況需要以乾粉吸入器、加壓定量吸入器、或以喷霧 器方式投藥。 ' 當以加壓吸入器方式投與類固醇時，呈微粉化形式較 佳。類固醇係懸浮或溶解於液體推進劑混合物中。可使用 之推進劑爲氟氣碳化物、煙類或氫氟境。特別佳之推進劑 經濟部中央標準局員工消費合作社印製 J---^-----"^衣-- (請先閲讀背面之注意事項再填寫本頁) -訂- 馬P134a(四氟乙烷）及P227(七氟丙烷），二者皆可單獨或 混合使用。它們亦可視情況併用並仑始 J推進劑、及/或界面 活性劑、及/或其它賦形劑，例如乙醇、 ^ 界面活性劑、潤 滑劑、抗氧化劑與穩定劑。 當以噴霧器方式使用類固醇時，類固醇可呈霧化水性縣 浮液或溶液狀態，可含有或不含pH或張力調整劑，呈單 -11 - 本紙張尺度適用中國國家標準（CNS ) A4im ( 210^297^· 568784 A7 ___ B7 五、發明説明（9 ) 位劑量或以多劑量裝置使用。 下列實例更詳細説明本發明。 實例1 患者爲5 3歲的老婦人’患有多年葦德氏症候群，但拒絕 接受手術方式治療她的息肉病，下腹上方稍微感到疼痛， 經局邵及全身性皮g類固醇治療後無效。但經由開藥每日 2 0毫克的歐米哌峻，加上每日2次，在每鼻孔每次投與 100微克的布松奈（budesonide)(水溶液）與每曰6毫克的狄 弗查克（deflazacort)治療2週後，患者感受到鼻子呼吸的問 題逐漸改善。最後息肉病完全治癒。 實例2到實例！ 〇 九位病患，各患有表1所列之症狀，接受爲期二個星期 的治療。該治療包括20毫克歐米喊唑、1〇〇微克鼻内吸入 布松奈及3〜5毫克口服狄弗查克（使用如此少量狄弗杳克 以確定病患的適應性）。其結果亦示於表1 —:I—：-------- (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 568784 五、發明説明（1〇 表n (ch3) 2 The H +, K + -ATPase inhibitor used in the present invention printed on the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is preferably of formula (la): In other words, the better one is omeprazole, or omega A basic salt of prazosazole, an enantiomer of omepramine, or a basic salt thereof. When the compound of formula (I) is a pharmaceutically acceptable basic salt as required, it is preferably a salt of Mg2 +, Ca2 +, Na +, K +, and more preferably a salt of Mg2 +. The H +, K + -ATPase inhibitors used in the present invention can be administered orally, rectally, or parenterally. Although the inhibitory effect of omeprazole on nasal polyps has been confirmed, Xianxin believes that the inhibitor has a systemic effect on polyps, regardless of the method of administration. Therefore, the effect of reducing the volume of polyps should still be achieved by other administration methods. Commercially available agents of H +, K + -ATPase inhibitors are suitable for use in the present invention. Examples of such omegaprazole preparations include enteric-coated pills of omegaprazole filled in capsules, or formulated as a unit unit tablet form; enteric-coated tablets or omegaprazole or its test salt; And non-enteric solution containing omegaprazole basic salt. The dosage of H +, K + -ATPase inhibitors depends on the type of nasal polyps being treated and the symptoms of the patient. However, the dosage for oral, rectal, or intravenous administration is generally 1 to 100 mg h +, k + -atp enzyme inhibition -9- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) J ^ clothing-(Please read the precautions on the back before filling out this page} Order 568784 A7 ------_ V. Description of the invention (7) ~ ^ " ---- The scope of the agent. Usually The oral dose is from 0 to 40 g per day. (Please read the precautions on the back before filling out this page) The present invention can be used in combination with other known diarrhea-like symptoms that are commonly associated with nasal polyposis, such as Other treatments for asthma. In other words, the present invention can be applied to treat Reed's syndrome, which includes symptoms of nasal polyposis, asthma, and aspirin sensitivity. The present invention can also be used to treat other diseases of upper respiratory tract inflammation Such as acute or chronic sinusitis, allergic or non-allergic rhinitis, and treatment of lower respiratory tract inflammation, such as asthma. Therefore, according to the present invention, a method for treating Reed's syndrome and other respiratory inflammatory diseases is provided, which includes treating patients At the same time, points Or continuously administer a pharmaceutical formulation containing Η +, κ + _ ATPg parent inhibitor and glucocorticoid. According to the present invention, a pharmaceutical formulation is further provided for simultaneous, separate or continuous administration of H + to a patient, K + -ATPase inhibitor and glucocorticoid formulations' for treating Reed's syndrome and asthma. The present invention also provides a h'k'atp enzyme inhibitor or glucocorticoids for the manufacture of these pharmaceutical formulations. Uses. Preferred glucocorticosteroids are locally active anti-inflammatory steroids. Examples of suitable steroids include budseonide; roHeponide; rofleponide palmitate; Ministry of Economic Affairs Ciclesonide printed by the Consumer Standards Cooperative of the Central Bureau of Standards; mometasone furoate; fluticasone propionate; 16 a, 17 α-butylene dioxy 1-6 Jiang, 9 from-^ Yiqi-lly5-, 21--via Gycnogenol-1, 4-Di-woman · 3, 20-dione; 6 from, 9 from-Difluoro-11々-hydroxy · 16α , 17α-dibutylene dioxy-17α-methylthio · androstane-4-en-3-one; S-16a, 17a-butylene Dioxy-6 α, 9 α -difluoro-11 Θ -Hydroxy-3-oxo-androstane-1,4-diene 17 /?-Carboxy-10- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 568784 A7 B7 V. Description of the invention (8) Methyl thio acid; 9α-gas-6sink-fluoro-11 from -¾yl-16shen-methyl_3-oxy-17 π-Propanyloxy-androstane-1,4-diene-17 π- double acid methyl ester; 6 α, 9 α _ difluoro- lly5 -¾yl-16α -methyl-3-oxy-17α -Propanyloxyandrostyl-1,4 · »difluorene-17 < ^-metathioic acid 8 _ (-2-oxo-tetrahydro-octane-38-yl) motive; dipdan (tipredane) Skin ease acetone (fiuocin〇i〇ne acet〇nide); flunisolide (flunisolide); flumethasone (flumethasone); dexamethasone; betamethasone (betamethasone); betamethasone dipropyl fe salt (beclomethasone dipropionate); deflazacort; cortivazol; or corticosteroid and / or cortisol, depending on the case, in its pure enantiomeric form (if the type When present) and in its pharmaceutically acceptable salt form. The steroids used in the present invention can be administered in conventional dosages, such as 40 to 300 micrograms per day. Administration can be by oral or intranasal inhalation. Steroids may be administered as a dry powder inhaler, a pressurized metered dose inhaler, or a nebulizer, as appropriate. '' When steroids are administered as a pressurized inhaler, micronized forms are preferred. Steroids are suspended or dissolved in a liquid propellant mixture. The propellants that can be used are fluorocarbons, smoke or hydrofluorocarbons. Special Good Propellant Printed by J --- ^ ----- " ^ 衣-by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy-(Please read the precautions on the back before filling out this page)-Order-Horse P134a (four Fluoroethane) and P227 (Heptafluoropropane), both of which can be used alone or in combination. They may also be used in combination with a Bronson propellant, and / or a surfactant, and / or other excipients, such as ethanol, surfactants, lubricants, antioxidants, and stabilizers. When steroids are used in the form of a sprayer, the steroids can be in the form of aerosolized liquid county floats or solutions, with or without pH or tonicity modifiers, in the form of a single -11-This paper applies Chinese National Standard (CNS) A4im (210 ^ 297 ^ · 568784 A7 ___ B7 V. Description of the invention (9) Dose or use in multi-dose devices. The following examples illustrate the present invention in more detail. However, she refused to undergo surgery to treat her polyposis. She felt a little pain in the upper abdomen, which was not effective after treatment with local steroids and systemic corticosteroids. However, she prescribed 20 mg of omegapone daily, plus 2 daily Second, after 100 weeks of budesonide (aqueous solution) and 6 mg of deflazacort per dose were administered to each nostril, the patient felt that his nose breathing problem gradually improved. Finally Polyposis was completely cured. Example 2 to Example! 〇 Nine patients, each with the symptoms listed in Table 1, received a two-week treatment. The treatment included 20 mg omegazol, 100 μg intranasal Introduce Boussonne and 3 to 5 mg of oral Diverchuck (using such a small amount of Divergent to determine the patient's fitness). The results are also shown in Table 1 —: I —: ------- -(Please read the precautions on the back before filling out this page) Order the paper size printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to apply the Chinese National Standard (CNS) A4 specification (210X297 mm) 568784 table
2IT 1 7 9 10 結果 董德氏症候 葦德氏症候 章德氏症候群 鼻部息肉病 鼻部息肉病 鼻部息肉病 鼻部息肉病 鼻邵息肉病及阿斯即靈過敏 鼻部息肉病及翁唑 暫時改善 正面效果 正面效果 長期的改善 無效 正面效果 正面效果 正面效果 無效 —j---^------- (請先閱讀背面之注意事項再填寫本頁} 訂 經確足爲正面效果者，表示該患者感受到鼻溢症狀降 低’此爲鼻部呼吸情況改善及鼻部息肉病體積縮小之明顯 改吾結果。經此治療後到暫時改善的患者，在停止使用歐 米喊唾及狄弗查克（局部消炎用類固醇、如布松奈 (budesodde)，依需要使用）後，出現息肉病再度復發的情 形。然而在治療後，恢復相同療程下，息肉體積則明顯縮 小 〇 經濟部中央標準局員工消費合作社印製 得到長期改善效果之實例5的病患。在最初的二星期治 療結束時，未顯示出改善的情形，但持續使用歐米哌唑， 二個月結束後顯示出正面效果。 -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 申請曰期 86. 10. 07. 案 號 086114622 類 別 (以上各欄由本局填註）2IT 1 7 9 10 ResultsDong De's Syndrome De De's Syndrome Chapter De's Syndrome Nasal Polyposis Nasal Polyposis Nasal Polyposis Nasal Polyposis Nasal Polyposis Nasal Polyposis and Aspid Allergic Nasal Polyposis and Weng Azole temporarily improves the positive effect, the long-term improvement is not effective, the positive effect, the positive effect, the positive effect is invalid—j --- ^ ------- (Please read the precautions on the back before filling this page} The effector said that the patient felt that the symptoms of rhinorrhea were reduced. This is a significant improvement of nasal breathing and a reduction in the volume of nasal polyposis. Patients who have temporarily improved after this treatment should stop using omega saliva and After Diffack (a topical anti-inflammatory steroid, such as budesodde, used as needed), polyposis recurred. However, after treatment, the volume of polyps decreased significantly after the same course of treatment was restored. Ministry of Economic Affairs Patients from the Central Standards Bureau Consumer Cooperative printed Example 5 with long-term improvement. At the end of the first two weeks of treatment, no improvement was shown but continued The use of Omeprazole showed a positive effect after the end of two months. -13- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Application date 86. 10. 07. Case No. 086114622 Category (above Each column is filled out by this bureau)
—U A4 C4 中文說明書替換頁(92年8月）568784 一、£2名稱 中 文 包含Η，Κ -ΑΤΡ酶抑制劑用於治療鼻部息丙病及葦孩灵^ 症候群之醫藥組合物 新型W 英 文 FHARMACEUlICAL COMPOSI1ION FOR l^ATlNG NASAL POLYPS AND WIDAL’S SYNDROME COMPRISIING IT，K+-ATPASE INHIBITOR" 姓 名 1.皮林德伯格 2·瓊恩皮納斯-馬沙 3·僑迪赛拉-卡爾拉斯 4.貞特羅非斯特 國 籍 1·4·瑞典 2.3.西班牙 -、發明人 一創作人 住、居所 1 ·瑞典蒙戴爾市高德斯高塔路4〇號 2·西班牙巴塞隆納市法蘭西斯馬歇爾廣場8號 3·西班牙巴塞隆納市派索皮爾三路71號 4.瑞典魯德市維本克羅根路34號 姓 名 (名稱） 瑞典商阿斯特捷利康公司 瑞典 國 籍 三、申請人 住、居所 (事務所^ 瑞典赛得特來S-15185克瓦伯蓋格街16號 代表人 姓 名 瑪格莉特•林德羅斯 -1 - 裝 訂—U A4 C4 Chinese Manual Replacement Page (August 1992) 568784 I. £ 2 Name in Chinese contains Η, κ-ΑΤΡ enzyme inhibitor for the treatment of nasal sigmoidosis and reed children ^ Syndrome new pharmaceutical composition W English FHARMACEUlICAL COMPOSI1ION FOR l ^ ATlNG NASAL POLYPS AND WIDAL'S SYNDROME COMPRISIING IT, K + -ATPASE INHIBITOR " Name 1. Pilindberg 2. Jon Pinas-Marsha 3. Qodisila-Carras 4. Jeanette Robust nationality 1.4 Sweden 2. Spain-, inventor-creator residence, domicile 1 No. 40 Gaodes Tower Road, Mundell, Sweden 2 France Marshall Square, Barcelona 8 No. 71, Paisopir 3rd Road, Barcelona, Spain 4. No. 34 Wibenkrogen Road, Ruder City, Sweden Name (Name) Swedish Trader Astorica Corporation Swedish Nationality III. Applicant's Residence and Residence (Office ^ Sadetel Sweden S-15185 Kvabergeg Street 16 Representative Name Margaret Linderos-1-Binding
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| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6846799B1 (en) * | 1998-08-18 | 2005-01-25 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
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